Slow-release matrix pellets and the production thereof

ABSTRACT

Slow-release matrix pellets with a spherical or lenticular shape and uniform maximum diameters in the range from 0.5 to 4 mm, composed ofa) 0.1-87% by weight of at least one biologically active compound,b) 5-50% by weight of at least one water-insoluble polymer,c) 5-45% by weight of at least one lipophilic component as plasticizer for polymer b),d) 3-40% by weight of a natural or semisynthetic gel former,e) 0-50% by weight of one or more conventional formulation aids.

The present invention relates to a solid, preferably pharmaceutical,slow-release form (pellets) in which the active substance is embedded ina mixture of a water-insoluble polymer, a lipid and a gel-formingpolymer which in water forms a highly viscous colloidal solution or atleast swells. Production takes place in a one-stage continuous processby melt extrusion and, preferably hot-cut shaping.

PRIOR ART

Matrix substances suitable for melt extrusion and slowing of release arepolymers and lipids which can be plasticized by pressure andtemperature. Speiser et al. describe in Pharm. Acta Helv. 46 (1971) 31the use of epoxy/amino resins which are soluble in gastric fluid andvinyl acetate/crotonic acid copolymers which are soluble in intestinalfluid for injection-molded drug forms (cf. in this connection what issaid about U.S. Pat. No. 3,432,592). Hüttenrauch and Schmeissinvestigated the release of model active substances from a polyethylenematrix produced by ram extrusion (Pharmazie 30 (1975) 229, 536). Mank etal. describe in Pharmazie 44 (1989) 773 and ibid. 45 (1990) 592 therelease of active substance from insoluble thermoplastic matrices. Thesemethods do not allow the slowing of release to be adjusted freely, andthe active substance is not completely released in particular from thepolyethylene matrices. In addition, this process has the disadvantagesof injection molding such as long residence time at high temperature andlarge material losses due to the feed channels whose contents must notbe reused. In addition, the tooling costs are extremely high relative tothe production rate.

N. A. El Gindy et al. describe in Acta Pharm. Technol. 33 (1987) 208-211the production of tablets by melting mixtures of active substances withwater-soluble (polyethylene glycols and polyoxyethylene/polyoxypropyleneblock copolymers) and insoluble polymers and subsequently compressing.Release from these forms is more or less rapid because of the choice ofpolymers. Production is by a batchwise process.

N. Follonier et al. report in Capsule News 1 (1991) 2 and in theAbstract of the 6th International Conference on PharmaceuticalTechnology, Paris, France, Jun. 2-4, 1992, the production of sustainedrelease pellets by melt extrusion from a single-screw extruder. Thesolidified extrudate was comminuted in a pelletizer. Water-insolublepolymers were used as matrix. Besides the size of the pellets, variousadditives were investigated to control release of the active substance.The polymer basis was principally an ethylene/vinyl acetate copolymer.However, it was not possible to achieve release by zero order kineticsof the active substance from these forms.

U.S. Pat. No. 3,432,592 describes the injection molding of polymer meltscontaining active substances. The polymers used therein are said to beat least partially soluble in the digestive fluids. The soluble polymermainly described is a complex condensation product of an amino diol andan epoxide, which is not customary in the drugs sector. Slowing ofrelease is achieved by also using thermoplastics of low solubility indigestive fluids. The polymer combinations indicated therein areunsuitable for slowing the release from pellets of active substanceswhich are readily soluble in water because the surface area/volume ratiois unfavorable. In general it is difficult to control the slowing ofrelease by this procedure, and when release is greatly slowed part ofthe active substance remains undissolved in the pellets (release ofactive substance obeys the {square root over (t)} law; see T. Higuchi,J. Pharm. Sci. 52 (1963) 1145-1149). Release by zero order kinetics isnot possible (cf. Table I).

EP-A 240 904 and EP-A 240 906 disclose the extrusion of polymer melts,preferably of vinylpyrrolidone copolymers, which contain activesubstances. There is no mention therein of the adjustment of aparticular profile of active substance release by means of polymermixtures. In addition, it has emerged that the storage stability of theproducts produced in this way is in many cases low, and therelease-slowing effect diminishes with time.

EP-B 204 596 describes the production of pellets by embedding an activesubstance in a matrix composed of the following components: at least onenon-hydrophilic polymer and either a mixture of at least two lipidsubstances, of which one has polymer-dissolving or -gelling propertiesand the other has lubricant properties, or one lipid substance whichcombines the two stated properties, with or without one or moreadditives selected from extenders and antistatic agents. Seriousdisadvantages: with higher amounts (above about 20%) of non-hydrophilicpolymer the release takes place too quickly for a slow-release product,and with smaller amounts the release changes greatly on storage and isincomplete.

It is an object of the present invention to produce pellets, preferablyfor pharmaceutical purposes, from which the active substance is releasedwith an adjustable release profile, ie. as slow as required, butcompletely. The intention was to achieve this aim by matrix pellets, ie.without release-slowing film coatings applied to the pellet core.

It is another object of the present invention, besides controlling therelease of active substance by the composition of the matrix (matrixslow-release pellets), to develop a technique for simple and low-costproduction of these pellets. It was intended that this take place in acontinuous and one-stage process without previous mixing orpregranulation of the components and without final spheronization orsimilar shaping/rounding of the pellets after the production process.

ACHIEVEMENT

We have found that this object is achieved in a simple manner by meltextrusion of certain polymer matrices which contain active substancesand subsequent continuous shaping to produce slow-release pellets withhigh active substance content, even of active substances which are veryreadily soluble in water, it being possible to achieve release profileswhich can be adjusted over wide ranges solely by the composition of thepolymer matrix without diffusion-controlling polymer coatings and whichhave high storage stability.

The basic principle of the polymer matrix according to the invention isa matrix which is plasticized by suitable lipophilic substances and iscomposed of a polymer which is insoluble in water and gastrointestinalfluids. In contrast to the prior art cited above, it is now possible toadjust the release profile freely over wide ranges if the matrix ofinsoluble polymer and lipophilic component additionally incorporates agel former, ie. a polymer which in water forms a highly viscous solution(hydrocolloid) or at least swells. With the prior art matrices, althoughthe release of the active substance is controlled by the concentrationof insoluble polymer, there is a risk that the administration form willdisintegrate if the amount of polymer is too low, but the release ofactive substance may be incomplete if the amount of polymer is toolarge, since portions of the active substance are completely entrappedand unavailable. The addition, according to the invention, of gel formerbreaks up the release-slowing matrix by swelling of this polymer, andthe active substance can be completely released (cf. Tab. I).

The polymer matrix according to the invention for matrix slow-releasepellets is a novel combination of inert, lipophilic and hydrophilicthermoplastic matrix.

The invention therefore relates to a solid pharmaceutical slow-releaseform (matrix pellets) produced in a single-stage process by meltextrusion in an extruder, preferably a twin-screw extruder or asingle-screw extruder with mixing section, at 50-200° C. with continuous(preferably hot-cut) shaping of a mixture of the following composition:

a) at least one biologically active compound (“active substance”;preferably in human or veterinary medicine, but also vitamins andsystemic insecticides, fungicides and herbicides) in an amount of0.1-87, preferably 1-75, in particular 45-75, % by weight,

b) at least one natural, semisynthetic or synthetic polymer which isinsoluble in water and gastrointestinal fluids, in an amount of 5-50,preferably 10-40, % by weight,

c) 5-45, preferably 10-35, % by weight of at least one water-insolublelipophilic component with plasticizer properties for polymer b) andlubricant properties,

d) 3-40, preferably 5-25, % by weight of at least one natural orsemisynthetic hydrophilic polymer which in water or gastrointestinalfluids forms highly viscous colloidal solutions or gels or at leastswells (abbreviated to “gel former” herein), and

e) 0-50, preferably 0-40, % by weight of one or more conventionalformulation auxiliaries.

The percentage data in each case are based on the total weight of thepellets.

Solid pharmaceutical slow-release forms for the purpose of the inventionare, for example, granules, preferably pellets, with delayed release ofactive substance. The resulting shaped articles can also be subsequentlymilled to a powder and used in this form (e.g. in hard gelatincapsules). Subsequent coating of the shaped articles with flavor-maskingfilm coatings as in the prior art (e.g. with polyacrylates, celluloseesters such as hydroxypropylmethylcellulose phthalates and celluloseethers such as ethylcellulose, hydroxypropylmethylcellulose orhydroxypropylcellulose) is not precluded but is as a general ruleunnecessary.

The pellets can in many cases be compressed to tablets. This compressionis suitable, inter alia, in cases where the dose of active substance ishigh and thus the resulting drug forms would be undesirably large. It ispossible by controlling the tabletting conditions (in particular thepressure) for individual pellets to disintegrate in some circumstances,so that the release of active substance does not have to be essentiallydifferent from analogous pellets which have been packed (loosely) incapsules. Compression to tablets leads to a reduction in volume of thedrug form, which may be advantageous in some cases. It is furthermorepossible, by adding osmotically active agents (e.g. inorganic salts), toobtain pellets which can be used as osmotically active swelling layer(cf. WO 92/04011) in order to bring about the release of activesubstance, e.g. from tablets (after compression) or capsules, by anosmosis principle.

Pharmaceutical active substances a) for the purpose of the inventionmean all substances with a pharmaceutical action and minimal sideeffects as long as they do not decompose under the processingconditions. The amount of active substance per dose unit and theconcentration can vary within wide limits depending on the activity anddesired rate of release. The only condition is that they are such toachieve the desired action. Thus, the active substance concentration canbe in the range from 0.1 to 87, preferably 1 to 80, in particular 45 to75, % by weight. Active substances for the purpose of the invention arealso, as mentioned, other biologically active compounds. Those preferredare betamethasone, thioctic acid, sotalol, salbutamol, norfenefrine,silymarin, dihydroergotamine, buflomedil, etofibrate, indomethacin,oxazepam, beta-acetyldigoxin, piroxicam, haloperidol, ISMN,amitriptyline, diclofenac, nifedipine, verapamil, pyritinol,nitrendipine, doxycycline, bromhexine, methylprednisolone, clonidine,fenofibrate, allopurinol, pirenzepine, levothyroxine, tamoxifen,metildigoxin, o-(beta-hydroxyethyl)rutoside, propicillin, aciclovirmononitrate, paracetamol, naftidrofuryl, pentoxyfylline, propafenone,acebutolol, L-thyroxine, tramadol, bromocriptine, loperamide, ketotifen,fenoterol, Ca dobesilate, propranolol, minocycline, nicergoline,ambroxol, metoprolol, beta-sitosterol, enalapril hydrogen maleate,bezafibrate, ISDN, gallopamil, xanthinol nicotinate, digitoxin,flunitrazepam, bencyclane, dexapanthenol, pindolol, lorazepam,diltiazem, piracetam, phenoxymethylpenicillin, furosemaide, bromazepam,flunarizine, erythromycin, metoclopramide, acemetacin, ranitidine,biperiden, metamizole, doxepin, dipotassium chlorazepate, tetrazepam,estramustine phosphate, terbutaline, captopril, maprotiline, prazosin,atenolol, glibenclamide, cefaclor, etilefrine, cimetidine, theophylline,hydromorphone, ibuprofen, primidone, clobazam, oxaceprol,medroxyprogesterone, flecainide, Mg pyridoxal 5-phosphate glutamate,hymecromone, etofylline clofibrate, vincamine, cinnarizine, diazepam,ketoprofen, flupentixol, molsidomine, glibornuride, dimetindene,melperone, soquinolol, dihydrocodeine, clomethiazole, clemastine,glisoxepide, kallidinogenase, oxyfedrine, baclofen,carboxymethylcysteine, thioridazine, betahistine, L-tryptophan, myrtol,bromelains, prenylamine, salazosulfapyridine, astemizole, sulpiride,benserazide, dibenzepin, acetylsalicylic acid, miconazole, nystatin,ketoconazole, Na picosulfate, colestyramine, gemfibrocil, rifampicin,fluorocortolone, mexiletine, amoxicillin, terfenadine,mucopolysaccharide polysulfates, triazolam, mianserin, tiaprofenic acid,amezinium metilsulfate, mefloquine, probucol, quinidine, carbamazepine,Mg L-aspartate, penbutolol, piretanide, amitriptyline, cyproterone, Navalproate, mebeverine, bisacodyl, 5-aminosalicylic acid, dihydralazine,magaldrate, phenprocoumon, amantadine, naproxen, carteolol, famotidine,methyldopa, auranofin, estriol, nadolol, levomepromazine, doxorubicin,meclofenoxate, azathioprine, flutamide, norfloxacin, fendiline,prajmalium bitartrate, escin.

Solid solutions of the following active substances are particularlypreferred: acetaminophen (=paracetamol), acetohexamide, acetyldigoxin,acetylsalicylic acid, acromycin, anipamil, benzocaine, beta-carotene,chloramphenicol, chlordiazepoxide, chlormadinone acetate, chlorthiazide,cinnarizine, clonazepam, codeine, dexamethasone, diazepam, dicumarol,digitoxin, digoxin, dihydroergotamine, drotaverine, flunitrazepam,furosemide, gramicidine, griseofulvin, hexobarbital,hydrochlorothiazide, hydrocortisone, hydroflumethazide, indomethacin,ketoprofen, lonetil, medazepam, mefruside, methandrostenolone,methylprednisolone, methylsulfadiazine (=sulfaperin), nalidixic acid,nifedipine, nitrazepam, nitrofurantoin, nystatin, estradiol, papaverine,phenacetin, phenobarbital, phenylbutazone, phenytoin, prednisone,reserpine, spironolactone, streptomycin, sulfadimidine(=sulfamethazine), sulfamethizole, sulfamethoxazole, sulfameter,sulfaperin, sulfathiazole, sulfisoxazole, testosterone, tolazamide,tolbutamide, trimethoprim, tyrothricin.

The term “solid solutions” is familiar to the skilled worker, see Chiouand Riegelman, J. Pharm. Sci. 60 (1971) 1281-1302. Active substances insolid solutions in polymers are present in a molecular dispersion in thematrix.

The natural, semisynthetic or synthetic polymer b) which is insoluble inwater and gastrointestinal fluids can be, for example, a cellulose ethersuch as ethylcellulose or a cellulose ester such as cellulose diacetate,cellulose triacetate, cellulose acetate propionate and cellulose acetatebutyrate. It is also possible to use insoluble polysaccharides such aschitin and chitin derivatives and microcrystalline cellulose. Examplesof suitable synthetic polymers are poly(meth)acrylates, homo- andcopolymers of vinyl acetate, and the like. Ethylcelluloses arepreferred.

The water-insoluble lipophilic component c) with plasticizing propertiesfor the polymer b) and lubricant properties can be, for example, a fattyalcohol such as cetyl or stearyl alcohol, a fatty acid such as stearicacid or a wax, for example ester wax based on montan wax. It is alsopossible to use according to the invention, for example, polyethoxylatedfatty alcohols, fatty acids and vegetable oils, hydrogenated vegetableoils, mono-, di- and triglycerides as well as lecithins. It isfurthermore possible to use polyglycerol fatty acid esters, saturatedpolyethoxylated glycerides, polyethylene oxides, polypropylene oxidesand block copolymers thereof, phthalic esters and acetylatedmonoglycerides. Mono-, di- or triglycerides or mixtures thereof andpolyglycerol fatty acid esters are preferred. Lipophilic components c)with an HLB (hydrophilic/lipophilic balance) of 1-9, in particular 2-5,are preferred.

Suitable gel formers d), ie. polymers which in water form highly viscouscolloidal solutions or gels or at least swell, are, in particular,water-soluble cellulose derivatives such as alkylcelluloses,hydroxyalkylcelluloses, hydroxyalkylalkylcelluloses, e.g.methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose,hydroxypropylcellulose, hydroxybutylcellulose,hydroxyethylmethylcellulose, hydroxypropylmethylcellulose; alsocarboxyalkylcelluloses, carboxyalkylalkylcelluloses,carboxyalkylcellulose esters, e.g. carboxymethylcellulose and its alkalimetal salts; they may also be other water-soluble polysaccharides suchas alginic acids and their salts (alginates), carrageenans, guar gum,xanthan gum, agar—agar, gum arabic and related gums, pectins,galactomannans, tragacanth, also water-soluble chitin derivatives suchas chitosan. Water-soluble alkylcelluloses, hydroxyalkylcelluloses orhydroxyalkylalkylcelluloses which as a 2% strength solution in water at20° C. have a viscosity of more than 1000 cps, preferably 3500-120,000cps, are preferred. Hydroxypropylmethylcelluloses with a degree ofmethylation of 1.36-1.81 and a degree of hydroxypropylation of0.12-0.23, as well as hydroxypropylcelluloses, are very particularlypreferred.

Synergistic increases in viscosity by mixing the polymeric components,for example hydroxypropylcelluloses with anionic polymers such ascarboxymethylcelluloses or sodium alginate, are particularlyadvantageous.

“Water-soluble” means that at least 0.5, preferably at least 2, grams ofthe polymer form a colloidal solution in 100 grams of water at 20° C.

Also suitable as polymer component d) are hydrophilic polymers which areinsoluble in water or intestinal fluids but swellable, such ascrosslinked polyvinylpyrrolidone or crosslinked starches, starchderivatives such as sodium starch glycolate, croscarmellose sodium,hydroxypropylcellulose with a low degree of substitution and crosslinkedsodium carboxymethylcellulose with a low degree of substitution.

It is crucial for the suitability of a polymer as component d) that, onthe one hand, it is hydrophilic and, on the other hand, it does notdissolve too rapidly in the digestive tract. On the one hand, it shouldpermit the active substance to diffuse out of the interior of thepellets but, on the other hand, this should take place only slowly. Thisis why it should form a gel or a highly viscous solution with water. Thechoice of this component and its amount has a crucial influence on therelease-slowing effect. It has emerged, surprisingly, that theabovementioned natural or semisynthetic hydrophilic gel-forming polymersensure, in contrast to completely synthetic polymers such as PVP orvinylpyrrolidone/vinyl acetate copolymers, high storage stability(release-slowing effect is constant on storage).

Component e) can be composed of one or more auxiliaries conventional forsuch purposes, such as fillers, lubricants, mold release agents,plasticizers, blowing agents, stabilizers, dyes, extenders, flowregulators and mixtures thereof. Examples of fillers are inorganicfillers such as the oxides of magnesium, aluminum, silicon, titaniumetc. and microcrystalline cellulose and cellulose powder, variousstarches and their breakdown products, (maltodextrins), lactose,mannitol and calcium diphosphate in a concentration of 0.02-50,preferably 0.20-20, % of the total weight of the pellets.

Examples of lubricants are stearates of aluminum and calcium, and talcand silicones in a concentration of 0.1-5, preferably 0.1-3, % of thetotal weight of the pellets.

Examples of plasticizers comprise low molecular weight poly(alkyleneoxides) such as poly(ethylene glycols), poly(propylene glycols),poly(ethylene/propylene glycols); organic plasticizers with a lowmolecular weight, such as glycerol, pentaerythritol, glycerolmonoacetate, diacetate or triacetate, propylene glycol, sorbitol, sodiumdiethyl sulfosuccinate, added in concentrations of 0.5-15, preferably0.5-5, % of the total weight of the pellets.

Examples of dyes are known azo dyes, organic and inorganic pigments, orcoloring matter of natural origin. Inorganic pigments are preferred andare present in concentrations of 0.001-10, preferably 0.5-3, % of thetotal weight of the pellets.

Auxiliaries also mean for the purpose of the invention substances forproducing a solid solution containing the pharmaceutical activesubstance. Examples of these auxiliaries are sugars and sugar alcoholssuch as mannitol, sorbitol, xylitol, also urea, pentaerythritol andpentaerythritol tetraacetate, polymers such as polyethylene oxides andpolypropylene oxides and block copolymers thereof (poloxamers),phosphatides such as lecithin, homo- and copolymers of vinylpyrrolidone,surfactants such as polyoxyethylene 40 stearate and citric and succinicacids, bile acids, sterols and others, as indicated, for example, in J.L. Ford, Pharm. Acta Helv. 61 (1986) 69-88.

Also regarded as pharmaceutical auxiliaries are bases or acids added tocontrol the solubility of an active substance (see, for example, K.Thoma et al., Pharm. Ind. 51 (1989) 98-101).

The active substance or substances can be mixed with the polymericbinders and, where appropriate, other conventional pharmaceuticaladditives before or after the melting of the polymeric binder byconventional industrial processes. The mixing preferably takes place inan extruder, preferably in a twin-screw extruder or a single-screwextruder with a mixing section.

The mixture of polymeric binders should, in the complete mixture of allthe components, soften or melt in the range from 50 to 200, preferably50 to 180, in particular 60 to 150, ° C. so that the composition can beextruded.

The melts contain no solvent. This means that no water and no organicsolvent is added.

The shaping takes place by melt extrusion at 50-200, preferably 50-180,in particular 60-150, ° C. and subsequent continuous forming to tablets,for example as described in EP-A 240 906 by passing the extrudatebetween two rolls driven in opposite directions with mutually opposingrecesses, whose design determines the shape of the tablets, in thesurface of the rolls. Cold-cut shaping is also suitable.

Hot-cut shaping is preferred. This entails the extrudates beingcomminuted immediately after emerging from the die arrangement on theextruder by, for example, rotating knives or another suitablearrangement, expediently into pieces whose length approximately equalsthe diameter of the extrudate. These cut-off melt particles cool in thestream of air or gas to such an extent that the surface is non-tacky oncontact with other particles or a vessel wall but, on the other hand,the particles are still sufficiently plastic to assume a spherical shapeowing to impacts, e.g. with the wall of a connected cyclone. Thisproduces in a straightforward manner substantially spherical orlenticular particles with diameters of 0.5-4, preferably 0.8-2, mm. Thepreferred smaller particles are primarily suitable for filling capsules.

The invention makes it possible to produce, in a simple andenvironmentally friendly manner (without solvent), slow-release matrixpellets which release the active substance in a manner which can becontrolled within wide limits. The release of active substance isdelayed without application of a controlling film coating, which wouldhave to be applied from organic solvents or aqueous dispersions andwould require a drying step. The release of active substance takes placeunder erosion and diffusion control. The invention makes it possible toachieve pH-independent release of active substance too. The formsaccording to the invention are suitable for active substances with verydifferent dissolving properties. The release-slowing effect can beadjusted extremely strictly even with small slow-release forms. Theprocess makes it possible to produce solid solutions of the activesubstances in the matrix polymer by melt technology without usingorganic solvents. Solid solutions are distinguished by improvedbioavailability. The process is very economic because it is continuous,and it is thus superior to traditional pelleting processes. The pelletsaccording to the invention can have a high content of active substance.The variation in release of active substance is small and excellentlyreproducible because of the high homogeneity of the compositions. Thekinetics of the release of active substance remain surprisingly stable(max 20% absolute difference in release, cf. Table II) even on storageunder extreme climatic conditions (storage for at least 1 month at 50°C. or at 30° C. and 75% relative humidity).

The advantages of the extrusion process compared with other techniquessuch as granulation and tableting are that the technology is simple,solvents are avoided, the number and amount of auxiliaries areminimized, it is possible to produce solid solutions, and there is nopossibility of the mixing of the components, in other words theindividual slow-release forms have a reliably uniform compositionthroughout manufacture. There are also the advantages of a continuousprocess with high throughput and low material losses.

EXAMPLES

The parts by weight indicated in the table of active substance, polymersand lipophilic component and other auxiliaries were either premixed orintroduced via separate weigh feeders directly into the feed section ofa twin-screw extruder (Werner & Pfleiderer, ZSK 30). Melt extrusion tookplace with a product throughput of about 3-4 kg/h. The temperatures ofthe individual zones (sections) of the extruder were 30/150/100/100/100°C., the temperature of the heated die strip being indicated separatelyin the table. The die strip had 7 boreholes each 1 mm in diameter. Theextrudates emerging through the heated die strip were pelleted byair-cooled hot-cut shaping using a granulator.

The release of active substance was measured by the USP XXI paddlemethod. This in vitro test method is used to determine the rate ofdissolution of shaped articles containing active substances, e.g.tablets.

This was done by maintaining 900 ml of a phosphate buffer of pH 6.8 at37° C. in a 1 l vessel with round bottom. A suitable amount of pellets(about 300 mg) 1.25-1.60 mm in size was weighed in. The percentagerelease of active substance from the pellets was determined in this USPXXI no-change test by UV spectroscopy after 1, 2, 3, 4, 5, 6, 7 and 8hours with the paddle rotating at 100 rpm.

TABLE I The active substance used in each of Examples 1 to 39 was 50% byweight gallopamil hydrochloride and in each of Examples 40 to 65 was 50%by weight theophylline. Insoluble Lipophilic Die Example polymercomponent Gel former temp. Release profile No. b) % c) % d) % [° C.] (%after 1 to 8 h) 1 Ethocel ® N 7 15 Precirol ® Ato 5 10 Klucel ® HF 25120 53/71/81/87/90/93/95/96 2 ″ 20 ″ 10 ″ 20 122 59/76/85/90/93/94/95/973 ″ 25 ″ 10 ″ 15 122 59/76/85/90/93/94/96/96 4 ″ 30 ″ 10 ″ 10 12562/79/87/92/94/96/97/97 5 ″ 35 ″ 10 ″ 5 124 63/77/84/88/90/92/94/95 6 ″10 ″ 15 ″ 25 125 52/70/80/85/89/93/95/96 7 ″ 15 ″ 15 ″ 20 11663/80/88/93/96/98/99/100 8 ″ 20 ″ 15 ″ 15 110 54/73/81/86/90/92/94/96 9″ 25 ″ 15 ″ 10 115 48/66/74/78/82/84/86/87 10 ″ 30 ″ 15 ″ 5 10431/43/49/54/57/59/61/63 11 ″ 10 ″ 20 ″ 20 65 38/55/66/73/78/82/85/87 12″ 15 ″ 20 ″ 15 67 32/46/56/62/67/71/74/76 13 ″ 20 ″ 20 ″ 10 8828/39/46/51/54/57/59/61 14 ″ 25 ″ 20 ″ 5 87 21/28/32/36/38/39/41/42 15 ″10 ″ 25 ″ 15 65 29/43/51/57/61/64/67/79 16 ″ 15 ″ 25 ″ 10 6123/33/40/45/48/50/52/55 17 ″ 20 ″ 25 ″ 5 59 17/23/27/30/33/34/35/38 18 ″10 ″ 30 ″ 10 58 23/34/41/46/50/53/55/57 19 ″ 15 ″ 30 ″ 5 5922/32/39/43/56/48/49/51 20 ″ 10 ″ 35 ″ 5 53 16/22/26/29/31/32/34/36 21 ″10 commercial 20 Klucel EF 20 90 36/49/56/61/65/68/71/73 long-chain par-tial glycerides 22 ″ 15 commercial 20 ″ 15 88 34/45/51/55/58/60/63/65long-chain par- tial glycerides 23 ″ 20 commercial 20 ″ 10 8831/39/44/47/49/51/53/55 long-chain par- tial glycerides 24 ″ 25commercial 20 ″ 5 64 22/26/28/30/31/32/33/33 long-chain par- tialglycerides 25 Avicel PH 101 20 commercial 20 Klucel HF 10 11869/88/96/100 long-chain par- tial glycerides 26 Ethylcellulose 10commercial 20 ″ 20 109 39/56/65/71/76/79/82/84 Type NF 100 long-chainpar- tial glycerides 27 Ethylcellulose 15 commercial 20 ″ 15 11024/37/46/52/60/62/64 Type NF 100 long-chain par- tial glycerides 28Ethylcellulose 20 commercial 20 ″ 10 110 20/27/32/34/37/38/40/41 Type NF100 long-chain par- tial glycerides 29 Ethylcellulose 25 commercial 20 ″5 110 15/20/22/23/24/25/26/28 Type NF 100 long-chain par- tialglycerides 30 Ethylcellulose 20 Polyglyceryl 20 ″ 10 10048/68/77/83/87/90/92/93 Type NF 7 3-distearate 31 Ethylcellulose 10Glycerol 20 ″ 20 100 33/54/67/76/83/87/92/94 Type NF 7 behenate 32Ethylcellulose 15 Glycerol 20 ″ 15 100 32/50/63/72/78/82/86/89 Type NF 7behenate 33 Ethylcellulose 20 Glycerol 20 ″ 10 10334/49/58/65/69/73/76/78 Type NF 7 behenate 34 Ethylcellulose 25 Glycerol20 ″ 5 103 29/40/47/52/56/59/62/63 Type NF 7 behenate 35 Ethylcellulose20 Polyglycerol 20 ″ 10 100 65/80/89/94/96/97/100/100 Type NF 7palmitostearate 36 Ethylcellulose 25 Polyglycolized 20 ″ 5 9853/68/77/83/86/89/91/93 Type NF 7 natural wax 37 Ethylcellulose 10Hydrogenated 20 ″ 15 80 33/54/66/75/80/83/86/88 Type NF 7 castor oil 38Ethylcellulose 26 Hydrogenated 20 ″ 10 85 30/47/59/67/73/76/79/82 TypeNF 7 castor oil 39 Ethylcellulose 25 Hydrogenated 20 ″ 5 9030/44/56/63/68/71/74/75 Type NF 7 castor oil 40 Ethocel N7 10 PrecirolAto5 20 Klucel HF 20 85 0/28/41/49/55/60/65/68/70 41 ″ 15 ″ 20 ″ 15 800/27/41/49/56/61/65/69/72 42 ″ 20 ″ 20 ″ 10 80 0/27/42/52/59/65/70/74/7743 ″ 25 ″ 20 ″ 5 80 0/24/36/44/49/54/58/62/65 44 ″ 10 ″ 20 Klucel EF 2080 0/53/74/85/92/95/98/100/100 45 ″ 15 ″ 20 ″ 15 850/45/61/72/79/85/89/92/93 46 ″ 20 ″ 20 ″ 10 85 0/26/35/42/47/51/54/58/6147 ″ 25 ″ 20 ″ 5 80 0/17/23/27/30/32/34/36/38 48 ″ 15 ″ 25 Klucel HF 1060 0/14/19/23/26/28/31/33/35 49 ″ 20 ″ 25 ″ 5 600/15/20/22/25/26/29/32/34 50 Ethocel N7 15 Precirol Ato5 30 ″ 5 600/9/13/15/17/19/21/23/25 51 Ethocel NF100 10 ″ 20 Klucel EF 20 800/27/42/51/58/65/68/74/77 52 ″ 15 ″ 20 ″ 15 89 0/18/27/32/36/41/43/47/5053 ″ 20 ″ 20 ″ 10 100 0/12/17/20/22/24/25/27/28 54 ″ 25 ″ 20 ″ 5 1150/6/8/9/10/11/11/12/12 55 ″ 10 ″ 25 ″ 15 88 0/17/27/33/38/41/45/45/50/5156 ″ 15 ″ 25 ″ 10 95 0/11/16/20/23/25/27/30/31 57 ″ 20 ″ 25 ″ 5 1000/7/10/11/13/14/15/16/16 58 Ethocel N7 10 hydrogenated 20 ″ 20 1050/52/76/88/93/95/97/98/99 castor oil 59 ″ 15 hydrogenated 20 ″ 15 900/40/56/65/73/79/83/88/89 castor oil 60 ″ 20 hydrogenated 20 ″ 10 870/27/39/48/54/59/64/69/72 castor oil 61 ″ 25 hydrogenated 20 ″ 5 850/14/20/24/28/32/35/38/41 castor oil 62 Ethocel NF100 10 hydrogenated 20″ 20 99 0/39/59/74/82/90/93/97/100 castor oil 63 ″ 15 hydrogenated 20 ″15 100 0/23/37/47/54/61/67/72/75 castor oil 64 ″ 20 hydrogenated 20 ″ 10110 0/13/16/24/29/32/35/38/40 castor oil 65 ″ 25 hydrogenated 20 ″ 5 1170/8/10/13/15/16/17/18/19 castor oil Ethocel ® = Ethylcellulose from Dow,USA Precirol ® Ato5 = Long-chain partial glyceride from Gattefossé,France Klucel ® = Hydroxypropylcellulose from Hercules, USA Avicel =Microcrystalline cellulose from FMC, USA

TABLE II Examples of the storage stability of the forms according to theinvention Release Release (% in 1 to 8 h) of (% after 1 to 8 h) of theExample the forms after stor- forms after storage (30° C., No. age (50°C. for 1 month) 75% rel. humidity for 1 month) 2126/46/58/65/71/74/77/80 25/37/45/51/56/60/63/65 2228/42/52/58/63/67/71/73 29/38/44/48/51/54/56/58 2321/32/39/44/48/51/53/55 26/34/41/43/45/47/48 24 15/20/23/25/27/29/31/3222/27/29/30/31/32/33/34 33 29/50/63/72/77/81/84/8634/48/58/64/70/72/75/77 34 28/45/55/61/67/70/74/7627/37/43/47/50/53/56/57 37 27/44/56/64/70/76/78/8026/40/50/58/63/67/71/74 38 27/45/58/67/74/77/81/8328/43/55/64/69/73/76/78 39 28/48/61/70/75/78/81/8327/40/50/57/61/64/67/69

TABLE III Comparative tests on the incomplete release from inerthydrophobic matrix without gel former Die Example Insoluble Lipophilictemp. Release profile No. Active substance polymer % component % [° C.](% after 1 to 8 h) 2 Gallopamil 50 Ethylcellulose Precirol Ato5 15 10718/22/25/27/29/30/31/32 hydrochloride Type NF7 3 Gallopamil 50Ethylcellulose 35 ″ 20 87 15/19/21/22/23/24/25/25 hydrochloride Type NF74 Gallopamil 50 Ethylcellulose 30 ″ 25 74 17/21/25/27/29/30/31/32hydrochloride Type NF7 5 Gallopamil 50 Ethylcellulose 25 ″ 30 5619/26/32/35/37/38/40/40 hydrochloride Type NF7 6 Gallopamil 50Ethylcellulose 20 ″ 35 57 15/21/26/29/30/31/33/33 hydrochloride Type NF77 Gallopamil 50 Ethylcellulose 15 hydrogenated 20 9519/28/35/41/45/48/51/53 hydrochloride Type NF7 castor oil 8 Gallopamil50 Ethylcellulose 30 Precirol Ato5 20 112 16/20/22/24/25/26/27hydrochloride Type NF100 9 Gallopamil 50 Ethylcellulose 30 Glycerol 20103 25/33/37/40/42/44/46/47 hydrochloride Type NF7 behenate 10Theophylline 50 Ethylcellulose 30 Precirol Ato5 20 8011/14/16/17/18/19/20/21 Type NF7 11 ″ 50 Ethylcellulose 30 ″ 20 1253/4/4/5/5/5/5/5/6 Type NF100 12 ″ 25 Ethylcellulose 25 ″ 25 1006/7/9/9/10/10/11/11 Type NF100 13 ″ 50 Ethylcellulose 30 hydrogenated 20140 2/3/3/3/4/4/4/4 Type NF100 castor oil 14 ″ 50 Ethylcellulose 30hydrogenated 20 95 4/5/5/6/7/7/7/8 Type NF7 castor oil

TABLE IV Comparative tests on the storage stability (as disclosed inEP-B 0 024 596) Release profile (% after 1 to 8 h) A Immediately afterproduction Ex Active Insoluble Lipophilic Non-hydrophilic B Storage at50° C. for No. substance % polymer % component % polymer II 1 month 1Gallopamil 50 Ethylcellulose 10 Precirol Ato5 20 Vinylpyrrolidone/ 20 Ahydrochloride Type NF7 vinyl acetate 45/60/67/72/76/78/81/83 copolymer B(Kollidon ® VA64) 52/69/76/81/84/86/88/90 2 Gallopamil 50 Ethylcellulose15 ″ 20 Vinylpyrrolidone/ 15 A hydrochloride Type NF7 vinyl acetate35/47/52/56/60/63/66/68 copolymer B (Kollidon ® VA64)41/62/72/76/79/81/83/84 3 Gallopamil 50 Ethylcellulose 20 ″ 20Vinylpyrrolidone/ 10 A hydrochloride Type NF7 vinyl acetate27/35/39/42/44/45/47/48 copolymer B (Kollidon ® VA64)28/44/54/61/67/70/73/75 4 Gallopamil 50 Ethylcellulose 25 20Vinylpyrrolidone/ 5 A hydrochloride Type NF7 vinyl acetate22/28/31/33/34/35/36/36 copolymer B (Kollidon ® VA64)14/24/32/38/43/47/51/54

We claim:
 1. Slow-release matrix pellets with a spherical or lenticularshape and uniform maximum diameters in the range of from 0.5 to 4 mm,said pellets comprising a) 0.1-87% by weight of at least onebiologically active compound, b) 5-50% by weight of ethylcellulose, c)5-45% by weight of at least one water insoluble lipophilic compound asplasticizer for polymer b) and lubricant, selected from the groupconsisting of mono-, di- triglycerides or mixtures thereof andpolyglycerol fatty acid esters, D) 3-40% by weight of a water solublecellulose derivative as a gel-forming polymer which breaks up therelease-slowing matrix by swelling of the ethylcellulose, said pelletsbeing obtained by extrusion of a solvent-free molten mixture of thecomponents at a temperature of from 50 to 200° C. and continuousshaping.
 2. Slow-release matrix pellets as claimed in claim 1, havingthe following concentrations of the components: a) 1-75% by weight, b)10-40% by weight, c) 10-35% by weight, d) 5-25% by weight. 3.Slow-release matrix pellets as claimed in claim 1, wherein the maximumdiameter is 0.8-2 mm.
 4. Slow-release matrix pellets as claimed in claim1 or 2, wherein the active substance (a) is pharmaceutical in nature. 5.A continuous one-stage process for producing slow-release matrix pelletsas claimed in claim 1 or 2 by extrusion of the molten mixture of thecomponents at 50-200° C. and continuous shaping.
 6. A process as claimedin claim 5, wherein extrusion is carried out at 50-180° C.
 7. A processas claimed in claim 5, wherein extrusion is carried out at 60-150° C. 8.A process as claimed in claim 5, wherein hot-cut shaping takes place. 9.Slow release pellets as claimed in claim 1, which after storage for onemonth at 50° C., release from 15 to 29% of said biologically activecompound in one hour and from 29 to 81%, respectively, after six hours.